The nervous system has functions that can be broadly categorized as motor, sensory and cognitive functions, and further subcategories can be determined within these groups. For example, normal motor functions relate to voluntary movements and reflex movements, and the anatomic substratum of voluntary movements involves two classes of neurons. The upper motor neurons carry impulses (messages) from the brain to the lower motor neurons located at all levels of the brain-stem and spinal cord. The lower motor neurons, in turn, as the "final common path" extend long axonal processes that command movement by voluntary muscles throughout the body. The voluntary movements are controlled by a finely-tuned system executing willed movements of the person, which can be perturbed in a number of ways.
Disorders of upper motor neurons and lower motor neurons affect not only voluntary movements, but also other circuits to allow excessive, undesired involuntary movements resulting in several types of involuntary movement disorders. Disorders of the upper motor neurons or lower motor neurons may be caused by:
(a) systemic damage preferentially involving certain neuronal systems (e.g., caused by metabolic, toxic, hereditary or other unknown mechanisms); or PA0 (b) non-systemic, non-preferential damage (e.g., caused by stroke, multiple sclerosis, meningitis, abscess, cerebral palsy, or injury of the brain or spinal cord at birth or later).
Whatever the actual cause of neurologic damage, abnormality of upper motor neuron function results in spasticity (causing slowness, stiffness and weakness of movement), commonly accompanied by clonus (repetitive involuntary movements) and muscle spasms. Abnormality of lower motor neuron function results in weakness, commonly associated with painful muscle cramps.
Treatment of clinical problems caused by upper motor neuron or lower motor neuron abnormality can be either disease-specific or non-specific. Effectiveness of a disease-specific treatment is confined to that disease (e.g., vitamin B.sub.12 in B.sub.12 deficiency), whereas non-specific treatment, termed "symptomatic treatment", benefits the symptoms regardless of causes (e.g., aspirin for headache and other pain, and antihypertensive drugs for various kinds of hypertension). Symptomatic treatment of upper motor neuron- or lower motor neuron-caused clinical abnormalities can improve motor (movement) functions in a wide variety of activities of daily living, such as walking, talking, swallowing, breathing and other arm, leg, neck and finger movements. Many of these abnormalities and symptoms in various diseases have not been alleviated or treated despite the advances in medicine in recent years.
For example, amyotrophic lateral sclerosis is a progressive terminal disease with both upper and lower motor neuron involvement. Adult-onset primary lateral sclerosis, adrenomyeloneuropathy and multiple sclerosis each involve upper motor neuron dysfunction. Lower motor neuron abnormalities are typical of juvenile proximal spinal muscular atrophy, chronic adult progressive muscular atrophy and chronic hereditary dysneuronal neuropathy (one form of Charcot-Marie-Tooth disease). Thus, it should be apparent that any therapeutic agent which would alleviate the motor neuron-related symptoms of such diseases would have broad applicability in the treatment of a wide variety of neurologic functions.
It is evident that in the above-described disorders, one set of motor symptoms may result from neuronal deterioration such as structural or functional abnormalities of the lower motor neurons (i.e., ventral horn or anterior horn neurons) or the lower motor neuron system (i.e., neuronal pathways influencing the lower motor neurons. In addition, another set of motor symptoms may result from abnormalities of the upper motor neurons, e.g., the corticospinal tracts and perhaps other suprasegmental pathways impinging on the lower motor neurons as the final common path.
While I do not wish to be bound to any particular theory, it appears that various neurologic disorders causing spasticity and/or weakness (for example, in both the hereditary and sporadic forms of amyotrophic lateral sclerosis) are associated with remediable biochemical defects.
According to the present invention, a replaceable transmitter-like and/or trophic-like moiety is provided for the improvement of neurologic function. Thyrotropin-releasing hormone is seen to comprise an active moiety that has been shown to produce marked improvement in neurologic and neuromuscular functions, particularly those caused by a deficiency in the function of either lower or upper neurons.
As described in the examples hereinafter set forth, thyrotropin-releasing hormone causes improvement of symptoms of malfunction of both lower and upper motor neurons. This improvement occurs in conditions involving lower motor neuron underactivity (e.g., muscle weakness) and overactivity (e.g., muscle cramps) as well as conditions related to defective activity of the upper motor neurons, for example, muscle spasticity, clonus, spasms, withdrawal reflexes and weakness.
Thyrotropin-releasing hormone (TRH), L-pyroglutamyl-L-histidyl-L-prolinamide) is a tripeptide with blocked N- and C-terminal residues, and is considered common to mammalian species including man. TRH has been isolated and identified from ovine and porcine hypothalami, and more recently has been synthesized de novo in the laboratory. It has been shown to have the following structure: ##STR1## Various aspects of the endocrinology of this hormone have been suggested, including the ability of hypothalamically-originating TRH to release not only thyroid-stimulating hormone but also prolactin from, respectively, thyrotrope and mammitrope cells in the anterior pituitary. In addition, it has been demonstrated that the distribution of TRH is not limited to the hypothalamus, but that more than seventy percent of the total TRH found in the central nervous system (brain and spinal cord) is extra-hypothalamic. Further studies have shown that TRH is also found in the gastro-intestinal tract, placenta, retina and other locations. In general, TRH has been suggested to play a neurotransmitter or neuromodulator role in the normal central nervous system, but has not been shown to be of any direct therapeutic benefit in the continuous treatment of neurologic disorders or pain.
Presently, TRH has been used only in certain tests to determine pituitary function in a single intravenous dosage of 300-500 .mu.g, and for this purpose is marketed as an aqueous solution containing 0.5 mg/ml TRH and 9.0 mg/ml sodium chloride adjusted to a neutral pH with hydrogen chloride.